ClinicoPathological Conference

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ClinicoPathological Conference

• 93-03-24
• ??? / ?????
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Chief complaints

• A 4-day-old girl had suffered from fever since
  two days ago

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Present illness (1)

• The 4-day-old female newborn was a fullterm and
  was delivered vaginally through thick meconium,
  with Apgar score of 9 at 1 minute and 9 at 5
  minute.
• She developed a fever of 38.6 C at 2 days of
  age, but was relatively well without
  cardiopulmonary compromise.
• She was sent to hospital for help where septic
  workup was done including lumbar puncture. Viral
  cultures were submitted because of several
  papulovesicular lesions noted on her back.
• Ampicillin gentamicine therapy was started at 2
  days of age and acyclovir was added at 4 days of
  age.
• All cultures including viral culture were
  negative.

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Present illness (2)

• Then she was transferred to another hospital for
  further evaluation.
• In addition, the mother had mild fever at the
  time of delivery, and was treated with
  antibiotics briefly before discharge.
• By telephone interview, the mother said that she
  was still febrile 1 week after delivery with the
  main symptoms of malaise, abdominal pain and
  headache.
• She denied respiratory symptoms, vomiting,
  diarrhea and skin rash. The father believed that
  she was jaundiced.

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Present illness (3)

• The baby continued to appear pale, ill and
  febrile. On the babys 10th day of life, the
  mother visited the nursery.
• With ill appearance, she told us that she had
  headache and neck pain.
• The father stated that she was having personality
  changes that began the week before delivery.
• The mother was then admitted to our hospital and
  evaluations revealed the diagnosis.

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Past, personal and family histories

• Fullterm with gestational age of 38 weeks via
  vaginal delivery.
• Apgar scores 9 9 at 1st 5th minutes,
  respectively BBW 3100 g
• Mother history a 24-year-old gravida 3, para 1
  to 2 mother.
• Contact history unknown
• Traveling history unknown
• Family history unknown

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Physical examinations(4 days of life)

• Vital signs HR 130 /min RR 40 /min BT
  38.6 C
• General appearance pale and ill-looking, fussy
  but consolable
• Skin several scabbing lesions on her scalp.
• Chest clear and symmetric breathing sound
  tachypnea (-) retraction (-)
• Abdomen palpable liver edge, 4 cm below the
  right costal margin in the midclavicular line
  palpable spleen tip, 3 cm below the left costal
  margin.
• Genitalia bilateral inguinal lymph nodes 0.5 cm
  in diameter

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Laboratory findings (1)

• At 3 days of age WBC 13400 /mm3Platelet
  96000 /mm3Neutrophil 48Lymphocytes 17
  Band form 29 (lt15 )
• ALT 20 U/L (6-50 U/L)
• CSF study WBC 4 /mm3 (all mononuclear
  cells)Protein 91 mg/dl (84 45 mg/dL)Glucose
  49 mg/dl (46 10 mg/dL)

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Laboratory findings (2)

• At 6 days of lifeCBC essentially
  unchangedAST 66 U/L (35-140 U/L)ALT 54
  U/L (6-50 U/L)r- GT 555 U/L (13-147 U/L)

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Problems of neonate

• Major problems
• Fever
• Skin lesions (papulovesicular) over the back
  scabbing lesions on the scalp
• Hepatosplenomegaly
• Lymphadenopathy over inguinal regions

• Minor problems
• Predominant band form of WBC
• Thrombocytopenia
• Heavy meconium stain

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Problems of mother

• Major problems
• Personality changes
• Fever when delivery s/p antibiotic therapy
• Still fever, malaise, abdominal pain and headache
• Headache and neck pain.

• Minor problems
• Jaundice

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Questions ??

• Neonate 1. any other abnormal physical findings
  ?2. head circumference ?3. ophthalmoscopic
  examination ?4. other laboratory findings (Hg,
  bilirubin etc..)5. CxR ?6. CNS image studies ?

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Question ??

• Mother 1. PROM ? Amnionitis ?2. Liver
  function ? Bilirubin levels ?3. fever source ?
  Genital cultures ?4. culture results ?5.
  physical findings ? Neurologic findings ? 6.
  Lumbar puncture ? CSF studies results? 7. past
  personal histories ? VDRL ?8. travel contact
  histories ?9. Image study (CxR, brain CT)? 10.
  What kind of antibiotics were used when
  delivery ? Drug history ?

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Possible Consequences of Infection of a Mother
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Possible organisms

• Bacteria Trepnema pallidum, Mycobacterium
  tuberculosis
• Virus Rubella, CMV, HSV, HIV, Enterovirus
• Protozoa Toxoplasma gondii, Plasmodium

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Clinical Features of Prenatal TORCH Infection
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Relative Clinical Features of TORCH Infection
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Congenital Rubella Syndrome

• Affect virtually all organ systems
• Manifestations 1.IUGR (most common)2.cataracts,
  frequently associated with microphthalmia
  3.myocarditis and structural cardiac defects
  (PDA or pulmonary artery stenosis)4.blueberry
  muffin skin lesions5.hearing loss from
  sensorineural deafness6.meningoencephalitis7.pne
  umonia, hepatitis, bone lucencies,
  thrombocytopenia purpura, and anemia.8.motor
  and mental retardation
• Diagnosis 1.anti-rubella IgM Ab in neonatal
  serum2.culturing rubella virus from the infant
  (nasopharynx, urine, or tissue)

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Cytomegalic Inclusion Disease

• Congenital CMV infection
• Only 5 of all congenitally infected infants have
  severe cytomegalic inclusion disease, another 5
  have mild involvement, and 90 are born with
  subclinical, but still chronic, CMV infection.
• Characteristic manifestations IUGR,
  prematurity, hepatosplenomegaly and jaundice,
  thrombocytopenia and purpura, and microcephaly
  and intracranial calcifications.
• Other neurologic problems chorioretinitis,
  sensorineural hearing loss, and mild increases in
  CSF protein
• Most symptomatic congenital infections and those
  resulting in sequelae are caused by primary
  rather than reactivated infections in pregnant
  women
• Re-infection with a different strain of CMV can
  lead to symptomatic congenital infection.
• Asymptomatic congenital CMV infection is likely a
  leading cause of sensorineural hearing loss,
  which occurs in approximately 7 of infected
  infants.

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Human Immunodeficiency Virus (1)

• Currently, gt95 of children with HIV infection
  acquire the infection from their mother (vertical
  transmission) transfusion of contaminated blood
  or clotting factor concentrates is now rarely
  observed in the USA
• Breastfeeding remains a possible risk for
  transmission.
• Infants born to HIV-infected mothers 1. Risk of
  infection is 13-39 if no antiretroviral therapy
  delivered to mother and infant2. With
  appropriate therapy, risk is lt 53. Risk factors
  for vertical transmission include maternal
  viral load and degree of immunodeficiency and
  PROM.

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Human Immunodeficiency Virus (2)

• Clinical manifestations 1. generally
  asymptomatic for first few months of life
  mean age of onset of symptoms is 1 year2. Common
  manifestations include failure to thrive,
  hepatosplenomegaly, oral candidiasis, recurrent
  diarrhea, recurrent bacterial infections, and
  PCP between 3-6 months of age.3. Anemia,
  neutropenia, and thrombocytopenia are common

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Possible organisms

• Bacteria Trepnema pallidum, Mycobacterium
  tuberculosis
• Virus Rubella, CMV, HSV, HIV, Enterovirus
• Protozoa Toxoplasma gondii, Plasmodium

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Enterovirus---NEONATAL INFECTIONS (1)

• Enterovirus infection frequently is with
  coxsackieviruses B2B5 and echoviruses 6, 9, 11,
  and 19.
• Transmission via 1. vertically before, during,
  or after delivery2. horizontally from other
  infected family members or by transmission in
  hospital nurseries (sporadic or epidemic).
• Infection in utero may be associated with
  placentitis, fetal demise, neonatal illness, and,
  possibly, congenital anomalies.
• Neonatal infection is associated with a range of
  clinical manifestations --- asymptomatic (the
  majority) --- benign febrile illness --- severe
  multi-system diseases
• Most affected newborns are full-term and
  previously well
• Maternal history often reveals a recent viral
  illness, including fever and, frequently,
  abdominal pain.

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Enterovirus---NEONATAL INFECTIONS (2)

• Symptoms in the neonate may occur throughout the
  newborn period, with some beginning as early as
  day 1 of life severe disease generally has an
  onset within the first 2 wk of life.
• Clinical manifestations --- fever or
  hypothermia, irritability, lethargy,
  anorexia,--- rash (maculopapular, occasionally
  petechial or papulovesicular),
  jaundice,--- respiratory symptoms, apnea,
  hepatomegaly, abdominal distention, emesis,
  diarrhea, and decreased perfusion.
• Most symptomatic neonates have benign courses,
  with resolution of fever in an average of 3 days
  and of other symptoms in about 1 wk.
  Occasionally, a biphasic course may occur.
• Laboratory findings --- leukocytosis,
  thrombocytopenia, pleocytosis, --- elevated
  transaminases and bilirubin, coagulopathy,---
  pulmonary infiltrates,--- EKG changes.

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Enterovirus---NEONATAL INFECTIONS (3)

• Complications include --- CNS necrosis and
  generalized or focal neurologic compromise---
  arrhythmias, congestive heart failure, myocardial
  infarction, and pericarditis --- hepatic
  necrosis and failure intracranial or other
  bleeding--- adrenal necrosis and hemorrhage
  and rapidly progressive pneumonitis. ---
  Myositis, NEC, SIADH, hemophagocytic syndrome,
  and sudden death are rare events.
• Mortality in those with severe disease is
  significant and is most often associated with
  hepatitis and associated bleeding complications,
  myocarditis, or pneumonitis.
• Risk factors for severe disease include ---
  illness onset in the first few days of life, ---
  maternal illness just prior to or at delivery,
  prematurity, male sex,--- infection by echovirus
  11 or a coxsackie B virus, --- positive serum
  viral culture, --- absence of neutralizing
  antibody to the infecting virus, --- evidence of
  severe hepatitis and/or multi-system disease.

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Congenital syphilis (1)

• Transplacental transmission of Treponema pallidum
  (spirochetes)
• Transmission can occur at any stage of pregnancy
  transmission rate approaching 100.
• Fetal and perinatal death occurs in 40 of
  affected infants.
• Clinical manifestations 1.early signs (during
  the first 2 yr of life) ---hepatosplenomegaly,
  jaundice, elevated liver enzymes bile stasis
  ---diffuse lymphadenopathy ---Coombs negative
  hemolytic anemia thrombocytopenia
  ---osteochondritis (wrist, elbow,ankle knee)
  and periostitis (long bone) ---mucocutaneous
  rash maculopapular or bullous lesions, followed
  by desquamation involving hands and feet
  ---CNS abnormalities, failure to thrive,
  chorioretinitis, nephritis2.late signs (appear
  gradually during the first 2 decades) ---result
  primarily from chronic inflammation of bone,
  teeth and CNS. ---olympian brow, Higoumenakis
  sign, saber shins, Hutchinson teeth, mulberry
  molars, saddle nose---Juvenile paresis, Juvenile
  tabes, Clutton joint

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Congenital syphilis (2)

• Diagnosis 1. nontreponemal tests ---VDRL,
  RPR ---detect Ab against a cardiolipin-cholester
  ol-lecithin complex ---helpful in
  screening ---titers elevate when active and
  decline when treatment is adequate2.
  treponemal tests ---TPI, FTA-ABS, and MHA-TP
  ---measure Ab specific to T. pallidum
  ---confirmatory testing of positive results from
  nontreponemal tests.

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Malaria

• Plasmodium protozoa (Plasmodium ovale, Plasmodium
  vivax, Plasmodium malariae, Plasmodium
  falciparum).
• Transmitted through 1. an infected female
  Anopheles species mosquito. 2. blood transfusion
  3. congenitally between mother and fetus (rare)
• Clinical manifestations 1. asymptomatic during
  the initial phase (incubation period)2.
  paroxysms of fever, rigors, sweats, headache,
  myalgia, back pain, abdominal pain, nausea,
  vomiting, diarrhea, pallor and jaundice.
• Diagnosis 1. identification of organisms on
  Giemsa-stained smears of peripheral blood2.
  monoclonal antibody test3. PCR

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Congenital malaria

• Malaria acquired from the mother prenatally or
  perinatally.
• In endemic areas, congenital malaria is an
  important cause of abortions, miscarriages,
  stillbirth, premature births, IUGR and neonatal
  deaths.
• Congenital malaria usually occurs in a nonimmune
  mother with P. vivax or P. malariae, although it
  can be observed with any of the human malaria
  species.
• Symptoms and signs most commonly occurs between
  10-30 days of age (14hr to several months of age)
• Clinical manifestations fever, restlessness,
  drowsiness, pallor, jaundice, poor feeding,
  vomiting, diarrhea, cyanosis and
  hepatosplenomegaly.

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Mycobacteria infection (1)

• Mycobacterium tuberculosis complex M.
  tuberculosis, M bovis, M africanum, M. microti,
  and M. canetti
• Transmission 1. person to person by airborne
  mucus droplet (most adults no longer
  transmit the organism within several days to 2 wk
  after chemotherapy)2. M. bovis may penetrate GI
  mucosa or invade lymphatic tissue of
  oropharynx (human infection is rare as a result
  of pasteurization of milk effective TB
  control program for cattle)
• Pregnancy and the newborn 1.congenital
  tuberculosis is rare because the most common
  result of female genital tract tuberculosis is
  infertility.2.primary infection just before or
  during pregnancy is more likely to cause
  congenital infection than is reactivation of a
  previous infection.3.tubercle bacilli first
  reach fetal liver, then pass into fetal
  circulation and infect many organs.4.congenita
  l tuberculosis may also be caused by aspiration
  or ingestion of infected amniotic fluid.

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Mycobacteria infection (2)

• Lymphohematogenous (disseminated) disease
  
• Tubercle bacilli are disseminated to distant
  sites, including liver, spleen,skin and lung
  apices, in all cases of tuberculosis infection.
• Lymphohematogenous spread is usually
  asymptomatic.
• Clinical manifestations ---hepatomegaly,
  splenomegaly---lymphadenitis in superficial or
  deep nodes---papulonecrotic tuberculids
  appearing on the skin---bone and joints or
  kidneys also may become involved---meningitis
  occurs only late in the course of the disease
• Miliary disease (the most clinically significant
  form of disseminated TB)---occurs when massive
  numbers of tubercle bacilli are released into
  bloodstream, causing disease in two or more
  organs.---occur within 2-6 mo of the initial
  infection---lesions are often larger and more
  numerous in the lungs, spleen, liver and bone
  marrow than other tissues.---chronic or
  recurrent headache (meningitis)---abdominal pain
  or tenderness (tuberculous peritonitis)---cutaneo
  us lesions papulonecrotic tuberculids, nodules,
  or purpura.

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Mycobacteria infection (3)

• Tuberculous
  Meningitis
• Tuberculosis of the CNS accounts for about 5 of
  extrapulmonary cases. It is seen most often in
  young children but also develops in adults,
  especially those who are infected with HIV.
• From hematogenous spread or rupture of a
  subependymal tubercle into the subarachnoid space
  .
• may present subtly as headache and mental changes
  or acutely as confusion, lethargy, altered
  sensorium, and neck rigidity.
• Typically, the disease evolves over 1 or 2 weeks,
  a course longer than that of bacterial
  meningitis Hydrocephalus is common .
• Lumbar puncture is the cornerstone of diagnosis.
• In general, CSF reveals a high leukocyte count, a
  protein content of 100 to 800 mg/dL, and a low
  glucose concentration.
• AFB are seen on direct smear of CSF sediment in
  only 20 of cases, but repeated lumbar punctures
  increase the yield. Culture of CSF is diagnostic
  in up to 80 of cases.
• CT and MRI may show hydrocephalus and abnormal
  enhancement of basal cisterns or ependyma

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---Congenital tuberculosis---

• symptoms may be present at birth but more
  commonly begin by the 2nd or 3rd wk of life.
• clinical manifestations respiratory distress,
  fever, hepatic or splenic enlargement, poor
  feeding, lethargy or irritability,
  lymphadenopathy, abdominal distention, failure
  to thrive, ear drainage, and skin lesions.
• Many infants have an abnormal chest radiograph,
  most often a miliary pattern.
• Some with no pulmonary findings early in the
  course of the disease later develop profound
  radiologic and clinical abnormalities.
• Clinical presentation of TB in newborn is similar
  to that caused by bacterial sepsis and other
  congenital infection, such as syphilis,
  toxoplasmosis and CMV.
• Diagnosis acid-fast stain of gastric aspirate,
  middle-ear discharge, bone marrow, tracheal
  aspirate, or biopsy tissue (especially liver)

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Impression

• 1.Mycobacteria tuberculosis
• 2.Enterovirus infection

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Diagnostic procedure

• AFB and culture of CSF from mother gastric
  aspirate from neonate
• PCR for enterovirus

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Thank you !!